The “Lost Decade” of Immunotherapy in Prostate Cancer and Emerging Signs of Hope
Editor’s Note: From November 10–16, 2025, the 9th West China Urologic Oncology Tianfu Academic Conference and the 11th Academic Conference on Urologic and Male Genitourinary Tumors of the Sichuan Anti-Cancer Association were grandly held in Chengdu. The meeting brought together leading experts in urologic oncology from China and abroad, providing a high-level platform for academic exchange. During the conference, Professor Yao Zhu from Fudan University Shanghai Cancer Center delivered a compelling lecture entitled “Evaluation of Immunotherapy in Prostate Cancer”. His presentation offered a critical analysis of the successes and failures of clinical research in this field over the past decade and provided forward-looking insights into future precision treatment strategies. This article is a comprehensive synthesis of Professor Zhu’s presentation.Reassessing the Status Quo: The “Darkest Hour” of Immunotherapy in Prostate Cancer
Within the comprehensive treatment landscape of prostate cancer, androgen deprivation therapy (ADT) has long remained the therapeutic cornerstone. Professor Zhu pointed out that nearly all combination strategies have historically attempted to position themselves as the “perfect partner” to ADT, aiming to achieve a synergistic “1 + 1 > 2” effect. However, a review of prior N-back studies and the latest clinical data invites serious reflection on the current state of immunotherapy in prostate cancer.
Professor Zhu first underscored a sobering reality: immune checkpoint inhibitors (ICIs) have extremely limited approved indications in prostate cancer. Unlike many other solid tumors, approvals for immunotherapy in prostate cancer are largely based on tumor-agnostic criteria—restricted to patients with mismatch repair deficiency (dMMR), microsatellite instability–high (MSI-H), or a tumor mutational burden (TMB) greater than 10 mutations per megabase. Unfortunately, such molecular features are exceedingly rare in prostate cancer, occurring in only about 1–2% of patients—far lower than in urothelial carcinoma, such as in Lynch syndrome–associated populations.
In addition, although antibody–drug conjugates (ADCs) like trastuzumab deruxtecan (T-DXd) may be considered for patients with high HER2 expression (IHC 3+), the overall conclusion remains clear: unselected prostate cancer populations are generally not suitable candidates for routine immunotherapy.
Revisiting the tumor immunity cycle theory published in Immunity, Professor Zhu noted that repeated failures in prostate cancer immunotherapy suggest that immune evasion in this disease is not driven by a single defective step, but rather by a systemic collapse across multiple stages of the immune response. This complexity implies that earlier research strategies focusing on single targets or isolated mechanisms were unlikely to succeed. As a result, the field faces profound challenges: when immune dysfunction spans multiple steps, how should appropriate control arms be designed? Should investigators modify the control treatment or redefine molecular selection criteria? These questions represent core unresolved issues in prostate cancer immunotherapy research.
Learning from History: Critical Lessons Behind Failed Clinical Trials
Professor Zhu described the exploration of immunotherapy in prostate cancer as “a series of costly trial-and-error experiments.” Beginning roughly 15 years ago with the advent of the CTLA-4 inhibitor ipilimumab, researchers tested numerous combination strategies, including combinations with tyrosine kinase inhibitors (TKIs), androgen receptor pathway inhibitors (ARPIs), PARP inhibitors, as well as chemotherapy or radiotherapy—each aiming to activate the immune microenvironment through different mechanisms.
Although many large phase III trials involving thousands of patients and enormous financial investment ultimately yielded negative results, Professor Zhu emphasized that the detailed data from these studies still offer valuable scientific insights.
First, in trials combining ipilimumab with radiotherapy, overall survival (OS) was not significantly improved. However, survival curves exhibited a pronounced “tail effect,” indicating that a subset of patients achieved long-term survival benefits after overcoming early toxicity. This observation suggests that reliance on traditional log-rank tests may obscure the long-term advantages of immunotherapy. Future studies should therefore focus on strategies to amplify late survival benefits while mitigating early adverse effects.
Second, trials combining immunotherapy with novel hormonal therapies revealed a puzzling outcome: overall survival in the combination arm was inferior to that of enzalutamide monotherapy. While radiographic imaging showed tumor shrinkage, prostate-specific antigen (PSA) levels did not decline in parallel. This discrepancy suggests that ARPIs may not remodel the tumor microenvironment in a manner that effectively activates T-cell–mediated immunity and may even introduce complex negative feedback mechanisms.
Additionally, studies combining chemotherapy with PD-1 inhibitors highlighted the challenge of control arm selection. Chemotherapy remains a standard treatment for advanced castration-resistant prostate cancer (CRPC), offering a median OS of approximately 19 months and a radiographic progression-free survival (rPFS) of 8.3 months. Any novel immunotherapy combination seeking to surpass chemotherapy in overall survival faces a formidable benchmark. Moreover, the relatively manageable toxicity profile of chemotherapy (grade ≥3 adverse events around 36%) further raises the bar for safety comparisons.
Precision Breakthrough: From Broad Populations to Molecularly Defined Subtypes
“Studies in unselected populations are destined to fail—precision selection is the key to progress,” Professor Zhu asserted, citing emerging clinical evidence that points to a new direction for prostate cancer immunotherapy.
The NEPTUNE study, published in Journal of Clinical Oncology (JCO) in 2024, marked a pivotal turning point. This study focused on three specific molecular subgroups: patients with dMMR/MSI-H tumors, those with biallelic DNA damage repair (DDR) mutations, and patients with high immune infiltration confirmed by immunohistochemistry.
Results showed a response rate of up to 70% in the dMMR population, compared with only about 10% in unselected prostate cancer patients. These findings provide compelling evidence that converting tumors from a proficient mismatch repair (pMMR) state to a dMMR-like phenotype could lead to a qualitative leap in therapeutic efficacy. Professor Zhu emphasized that dMMR tumors represent not only the therapeutic “gold standard” but also the optimal reference model for future research. By understanding why dMMR tumors respond—and how resistance eventually develops—researchers may reverse-engineer the missing immune components in other prostate cancer subtypes.
Similarly, the INSPIRE study demonstrated that BRCA mutations alone are insufficient; only biallelic loss generates adequate immunogenicity. Together, these studies are driving a paradigm shift from “one-size-fits-all” drug development toward refined molecular stratification in prostate cancer.
Looking Ahead: The Rise of Bispecific Antibodies and Novel Therapeutic Platforms
When discussing future research frontiers, Professor Zhu highlighted the breakthrough potential of T-cell engagers (TCEs) in prostate cancer. One of the most promising strategies to transform prostate cancer from an immunologically “cold” tumor into a “hot” one is to forcibly recruit T cells into the tumor microenvironment.
Professor Zhu drew particular attention to a study on a KLK2/CD3 bispecific antibody (JNJ-78278343), submitted in May and accepted by JCO in June of the same year. This agent not only demonstrated encouraging antitumor activity but also showed a favorable safety profile, with grade ≥3 cytokine release syndrome (CRS) occurring in only 8.9% of patients. This is especially significant given that dual immune checkpoint blockade (PD-1 plus CTLA-4), while effective, has been limited by excessive toxicity.
Currently, five clinical trials are underway for this agent, including two large phase III studies evaluating its efficacy in the late-line setting and in combination with chemotherapy. The emergence of such therapies signals a new era in prostate cancer immunotherapy—one characterized by advanced antibody engineering and more precise therapeutic combinations.
Conclusion and Outlook
In his concluding remarks, Professor Zhu candidly acknowledged that all phase III immunotherapy trials in prostate cancer to date have failed. However, this does not imply that immunotherapy has no role in this disease. The 70% response rate observed in dMMR patients stands as a beacon, illuminating the path forward.
Future research should focus on three key dimensions:
- More precise patient selection, using molecular characteristics to redefine target populations;
- More rational control-arm design, accounting for the multi-step nature of immune dysfunction;
- More innovative therapeutic modalities, including T-cell engagers (bispecific antibodies) and radioligand conjugates.
Prostate cancer immunotherapy is undergoing a transition from blind exploration to rational reorientation. As our understanding of the tumor immune microenvironment deepens, there is strong reason to believe that agents with breakthrough potential—such as JNJ-78278343—may ultimately overcome longstanding barriers and offer durable survival benefits for patients with advanced prostate cancer.
Professor Yao Zhu
